Sunday, February 12, 2023

How The WHO & CDC Are Developing Candidate H5N1 Vaccines

BSL-3 – Credit CDC PHIL


With HPAI H5 continuing to make inroads into mammalian species, and growing concerns that it might eventually evolve into a bigger threat to public health, a lot of people are asking about the availability or creation of emergency H5N1 vaccines.

The good news is, researchers have been creating H5N1 vaccines for nearly 20 years.  The not-quite-as-good news is, these vaccines have not always proved to be as effective - or as easy to manufacture - as we might hope.

Vaccine technology has admittedly improved significantly over the past two decades. The successful creation and delivery of multiple SARS-CoV-2 vaccines within 12 months of the outbreak of COVID proves that. 

But the creation of each new vaccine presents unique challenges, and success is far from guaranteed.  

While many countries are moving towards using H5N1 vaccines to protect their poultry industry, today's discussion focuses on the development of a pandemic vaccine for humans. 

The enormous task of bulk manufacturing of vaccines (including fill and finish) is left to large pharmaceutical companies, but before any of that can happen the CDC, WHO, and other health partners must select, genetically modify, antigenically test and approve candidate vaccine viruses (CVVs). 

The first and arguably biggest obstacle is, HPAI H5 is continually evolving. 

Even though we refer to the current threat as a fairly specific H5N1 clade, there are numerous genotypes and antigenic variants within this clade. The WHO described the growing diversity within the H5N1 subtype last August.

Clade viruses were detected in birds in many countries in Africa, Asia, Europe and North America. Additionally, viruses were detected in non-human mammals in some countries in Asia, Europe and North America. Viruses from Canada and the United States of America had HAs that were genetically similar to the A/Astrakhan/3212/2020 CVV (Fig. 1).

However, geographical clustering of phylogenetic groups has become increasingly pronounced and viruses from some countries in eastern Europe and West Africa, Cambodia and Viet Nam were less well recognized by an antiserum raised against the A/Astrakhan/3212/2020 CVV. The viruses from eastern Europe and West Africa were well recognized by post-infection ferret antisera raised against recent viruses circulating in poultry in West Africa (Table 2).

Since then we've seen even more diverse H5N1 viruses emerge (see Preprint: Rapid Evolution of A(H5N1) Influenza Viruses After Intercontinental Spread to North America), making it entirely possible that if a pandemic vaccine is required - it will be for a strain that has not yet emerged. 

Despite this constant evolution, in order to shave time off the manufacturing of a pandemic vaccine, the WHO, CDC, and others continually analyze emerging novel viruses and have selected dozens over the years to turn into a candidate vaccine virus (see 2015's CDC: Making a Candidate Vaccine Virus For HPAI Avian Flu).

Since H5N1 reemerged in 2003, more than three dozen H5 CVVs have been selected by WHO for development. Most of those viruses are now extinct, making this an expensive proposition, but having an already approved CVV can save weeks or even months of valuable time if mass production and distribution of a vaccine is ever required.

Similarly there are currently 22 H7Nx CVVs either available or under development, and 9 H9N2 CVVs either developed or in the pipeline.  Other novel viruses, including swine variant H1 and H3 viruses, have CVVs as well.
Along the way, some of these CVVs have been used to create (usually small) stockpiles of vaccines.  However, with a limited shelf life, and the rapid evolution of viruses in the field, it is impractical to manufacture and store large quantities of any of these vaccines. 

Whatever stockpiles might be available at the start of a pandemic would likely only be a partial match to the virus, and limited in quantity.  That said, they might still be useful to provide initial protection to key researchers and other front line workers in the opening months of a pandemic. 

Experimental H5 and H7 avian flu vaccines have proved poorly immunogenic in the past – requiring unusually large amounts of antigen (up to 12x normal) or an adjuvant - spread across two shots several weeks apart - to induce a good immune response (see 2013's FDA Approves Adjuvanted H5N1 Vaccine For National Stockpile)

Additionally, we've seen problems manufacturing H5N1 vaccine in bulk (see 2019's Manufacturing Pandemic Flu Vaccines: Easier Said Than Done), particularly in egg-based production facilities.

Despite all of these obstacles, it is likely that a new H5N1 vaccine could be made available in some quantity within 6 months of an outbreak. How effective it will be, and how quickly production can be ramped up, remain to be seen. 

As I warned back in 2020 in A COVID Vaccine Reality Check, we have a problem with over-promising when it comes to vaccine effectiveness. So much so that a vaccine that prevents 50% of infections - and saves millions of lives - might still be viewed as a `failure' by the public.  

While H5N1 has the potential to produce a deadlier pandemic than COVID, some of the claims on social media that it kills `50% of those who are infected' are badly overblown.  At worst, it kills 50% of those sick enough to be hospitalized, an important distinction that I go into at some length in Revisiting the H5N1 CFR (Case Fatality Rate) Debate.  

Fortunately, we have several influenza antivirals (oseltamivir,  oral baloxavir, inhaled zanamivir, or intravenous peramivir) that are expected to significantly reduce morbidity and mortality from H5N1.

Whether we will have enough, and are able to get them to the people who will need it within 48 hours of falling ill (see last December's CDC HAN #0482: Prioritizing Antiviral Treatment of Influenza in the Setting of Reduced Availability of Oseltamivir), are unknowns.   

Below you'll find a couple of links from the CDC that provide greater detail on their vaccine development efforts. I'll have a postscript after the break. 

The U.S. federal government maintains a stockpile of vaccines, including vaccines against A(H5N1) and A(H7N9) bird flu viruses. These vaccines could be used if similar viruses were to begin spreading easily from person to person. Since flu viruses change constantly, CDC continues to make candidate vaccine viruses (CVVs) as needed. Creating a CVV is the first step in producing a flu vaccine. More information about Making a candidate Vaccine Virus (CVV) for a Highly Pathogenic Avian Influenza (Bird Flu) Virus is available.


Making a Candidate Vaccine Virus (CVV) for a HPAI (Bird Flu) Virus 

A candidate vaccine virus (CVV) is an influenza (flu) virus that has been prepared by CDC or another public health partner that can be used by vaccine manufacturers to produce a flu vaccine. In addition to preparing CVVs for seasonal flu vaccine production, CDC routinely develops CVVs for novel avian influenza (bird flu) viruses with pandemic potential as part of pandemic preparedness activities. Some novel bird flu viruses with pandemic potential are “highly pathogenic avian influenza” (HPAI) viruses, which means they are deadly to domestic poultry, including chickens. Data collected through global and animal flu surveillance informs the selection of CVVs, and experts choose CVVs against bird flu viruses in nature (“wild type” viruses) that pose a risk to human health.

The creation of a CVV for a novel bird flu virus is a multistep process that takes months, from start to finish. Creating a bird flu CVV is usually more complicated than the process for creating a seasonal flu CVV. There are five steps involved in the creation of a bird flu CVV, including the following:

H5N1 is obviously not guaranteed to become the next global health threat, and the next pandemic may not even arise from an influenza virus. There are plenty of other candidates, including MERS-CoV, Nipah, Langya, Lassa Fever, and even Virus X - the one we don't know about yet

Hopefully we have a few years before that happens, so that we can finish dealing with the COVID emergency, and have time to process and recover physically, emotionally, and economically from the past 3 years.   

But viruses don't care one whit about our problems, and the next global health crisis could already be simmering, ignored or unrecognized, in some remote corner of the world waiting to board an airliner to begin its world tour.   

While it may not happen today, or tomorrow - given the stakes - we need to be preparing for it as if it could.